Protease Inhibitors

Tipranavir (Aptivus, TPV)

Carcinogenicity
Tipranavir was neither mutagenic nor clastogenic in a battery of five in vitro and animal in vivo screening tests. Long-term carcinogenicity studies in mice and rats have been conducted with tipranavir. Mice were administered doses ranging from 30 to 300 mg/kg/day tipranavir, with or without 40 mg/kg/day ritonavir; all doses resulted in systemic exposures below those in humans receiving the recommended dose. Incidence of benign hepatocellular adenomas, combined adenomas/carcinomas, and hepatocellular carcinoma was increased in both sexes with tipranavir/ritonavir. The clinical relevance of the carcinogenic findings in mice is unknown. Rats were administered doses ranging from 30 to 300 mg/kg/day tipranavir, with or without ritonavir. No drug-related findings were observed in male rats. At the highest dose of tipranavir (approximately equivalent to exposure in humans at the recommended therapeutic dose), an increased incidence of benign follicular cell adenomas of the thyroid gland was observed in female rats. This finding is probably not relevant to humans because thyroid follicular cell adenomas are considered a rodent-specific effect secondary to enzyme induction.1

Reproduction/Fertility
Tipranavir had no effect on fertility or early embryonic development in rats at exposure levels similar to human exposures at the recommended clinical dose (500/200 mg of tipranavir/ritonavir administered twice daily).1

Teratogenicity/Adverse Pregnancy Outcomes
No teratogenicity was detected in studies of pregnant rats and rabbits at exposure levels approximately 1.1-fold and 0.1-fold human exposure. Fetal toxicity (decreased ossification and body weights) was observed in rats exposed to 400 mg/kg/day or more of tipranavir (~0.8-fold human exposure). Fetal toxicity was not seen in rats and rabbits at levels of 0.2-fold and 0.1-fold human exposures. In rats, no adverse effects on development were seen at levels of 40 mg/kg/day (~0.2-fold human exposure), but at 400 mg/kg/day (~0.8-fold human exposure), growth inhibition in pups and maternal toxicity were seen.1

Placental and Breast Milk Passage
No animal studies of placental or breast milk passage of tipranavir have been reported.

Human Studies in Pregnancy

Pharmacokinetics
No studies of tipranavir have been completed in pregnant women or neonates.

Placental and Breast Milk Passage
It is unknown if passage of tipranavir through the placenta or breast milk occurs in humans. A single case report described relatively high levels of tipranavir in the third trimester and relatively high placental transfer (0.41), as measured by cord blood.2

Teratogenicity/Adverse Pregnancy Outcomes
The four first-trimester exposures to tipranavir that have been monitored to date in the Antiretroviral Pregnancy Registry are insufficient to allow conclusions to be drawn regarding risk of birth defects.3